A chemotrascriptomic screening identifies the reversal of glucocorticoid resistance in NOTCH1 mutated T-ALL.

Background: Gain-of-function NOTCH1 mutations are the most common genetic abnormality in T-cell Acute Lymphoblastic Leukemia (T-ALL), accounting for 55-60% of the cases. Consequently, modulators of the Notch pathway, such as γ -secretase inhibitors (GSI), would be expected to have clinical efficacy (Rao, Cancer Res 2009). However, their application was limited by an excess of toxicity due to the suppression of wild-type (WT) NOTCH1 proteins in normal tissue (Deangelo, JCO 2006; Doody, Alzherimer's Res Ther 2015). In the past, we identified the Sarco-Endoplasmic Ca2+ ATPase (SERCA) as a gatekeeper of the oncogenic Notch1 signaling. Thapsigargin (TG), a potent SERCA inhibitor (SI), possesses an anti-NOTCH1-leukemia activity both in vitro and in vivo by preferentially targeting mutated NOTCH1 proteins over WT ones (Roti, Cancer Cell 2013). Aims: Since SIs display a favorable therapeutic index by targeting mutated NOTCH1 proteins, development of new SIs is under preclinical development (Marchesini, Cell Chem Biol 2020). Thus, is important to establish molecular mechanisms portending resistance in order to develop effective therapeutic strategies to overcome or prevent drug resistance.